Factor derived from human lung carcinoma associated with hypercalcemia mimics the effects of parathyroid hormone on phosphate transport in cultured renal epithelia.

A decrease in renal tubular reabsorption of inorganic phosphate (Pi) can be observed in hypercalcemia of malignancy. In the present study we investigated the effect of serum-free conditioned medium (CM) from cells, derived from a lung carcinoma (BEN) of a hypercalcemic patient, and of PTH on cyclic AMP (cAMP) production and sodium-dependent Pi transport (NaPiT) in epithelia of two renal cell lines. In opossum kidney cells (OK), PTH is known to enhance cAMP production and inhibit NaPiT; in contrast, in LLC-PK1 cells, PTH has no effect on NaPiT since this kidney cell line is devoid of PTH receptors.

Parathyroid hormone-independent regulation of 1,25(OH)2D in response to inhibition of bone resorption.

Both plasma level of 1,25-dihydroxyvitamin D [1,25(OH)2D] and intestinal Ca absorption increase after biphosphonate-induced inhibition of bone resorption. Parathyroid hormone (PTH) has been considered a key mediating element of this homeostatic response. In the present work, the role of PTH was assessed by studying the influence of 1-hydroxypentane-1,1-bisphosphonate (HPeBP) on vitamin D and Ca metabolism in both intact and thyroparathyroidectomized (TPTX) rats.

Influence of calcium on phosphate transport in cultured kidney epithelium.

Renal epithelia cultured from opossum kidney (OK) cell line were exposed to high- and low-Ca media (HCaM and LCaM, respectively). Changing the extracellular Ca concentration from 2.0 mM to 0.

Effect of long-term treatment with antiepileptic drugs on the vitamin status.

The status of vitamins A, B1, B2, B6, B12, C, D, and E as well as that of beta-carotene, biotin, and folate in the blood of over 500 epileptics was compared with that of a normal population. Male and female epileptics showed a poorer supply of vitamins B2, biotin, folate, and 25-hydroxycholecalciferol; the males, of only vitamin B6, B12, and E, and the women, of only vitamin A. Concentrations of beta-carotene and vitamin E in female epileptics were higher.

Bone and renal components in hypercalcemia of malignancy and responses to a single infusion of clodronate.

Increased bone resorption (BR) and increased renal tubular reabsorption of calcium (TRCa) may both be involved in the pathogenesis of hypercalcemia of malignancy (HM). We have evaluated the relative importance of these two mechanisms in 33 patients with HM after extracellular volume expansion and after single infusion of clodronate (C12MDP: 500 mg iv over 8 h). The fasting urine Ca/creatinine ratio was taken as an index of BR (BRI).

Interference of WR-2721 with magnesium metabolism: mechanism of action.

Recently, a radio-, and chemoprotective drug, WR-2721 (S-2-[3-aminopropylamino]-,ethylphosphorothioic acid) proved to be a potent inhibitor of parathyroid hormone (PTH) secretion. In human subjects, it not only decreased plasma Ca, but also induced a significant fall in the plasma magnesium level. In the present study in rats we investigated the mechanism(s) of this hypomagnesemic effect.

The increase in skin 7-dehydrocholesterol induced by an hypocholesterolemic agent is associated with elevated 25-hydroxyvitamin D3 plasma level.

Vitamin D3 is generated in skin by UV irradiation of 7-dehydrocholesterol (7-DEHC). Whether the 7-DEHC amount in skin affects vitamin D3 formation, and thereby the plasma level of 25-hydroxyvitamin D3 (25[OH]D3) is not known. In the present work we report on the influence on vitamin D and Ca metabolism of a new hypocholesterolemic agent, HCG-917 (0-2-[hydroxy-3-]N'-(2-chlorophenyl)-N-piperazinyl-1- [propyl]-4-chloro-benz-aldoxim-hydrochloride) which inhibits 7-DEHC reductase and thereby increases skin 7-DEHC.

Effect of dexamethasone on parathyroid hormone stimulation of cyclic AMP in an opossum kidney cell line.

The influence of the glucocorticoid dexamethasone on the cAMP response to parathyroid hormone (PTH) and various agonists was studied in epithelial monolayers of opossum kidney (OK) cells. The incubation with dexamethasone for 72 hours led to a dose-dependent higher cAMP response to PTH or forskolin in intact cells as well as in digitonin-permeabilized cells. This effect did not appear to result from changes in phosphodiesterase (PDE) activity nor from alterations in cAMP efflux from the cells.

Adaptation of phosphate transport to low phosphate diet in renal and intestinal brush border membrane vesicles: influence of sodium and pH.

The possible role of changes in the sodium (Na) affinity of the carrier for inorganic phosphate (Pi) in the adaptation of Pi transport to low Pi diet was examined in both renal and intestinal brush border membranes vesicles (BBMV) obtained from the same animal. This role was assessed by measuring the Na concentration resulting in half maximal activation of Pi transport (K0.5 Na) in renal and intestinal BBMV prepared from animals adapted to either low (LPD) or high (HPD) phosphorus diet for 7 days.

Interleukin-1 decreases renal sodium reabsorption: possible mechanism of endotoxin-induced natriuresis.

Administration of pyrogen or endotoxins such as Escherichia coli lipopolysaccharide can elicit a marked increase in urinary sodium excretion. This response occurs without any elevation in the filtered load of sodium and it does not appear to be prostaglandin mediated. The various effects produced by endotoxins appear to have interleukin-1 as a common mediator.

Prevention of parathyroid hormone-dependent nephrocalcinosis by chronic administration of the organic phosphorothioate WR-2721.

Pharmacological inhibition of parathyroid hormone (PTH) secretion has been the object of several experimental and clinical trials in the past. It is only recently that a drug, WR-2721 [S-,2-(3-aminopropylamino)-,ethylphosphorothioic acid], has been shown to effectively inhibit PTH secretion in euparathyroid subjects and in parathyroid cancer patients within a few hours after its administration. In the present study we tested its long term efficacy as a PTH inhibitor in a model of nephrocalcinosis resulting from secondary hyperparathyroidism.

Effects of glucagon on renal and extrarenal handling of inorganic phosphate in mice: evidence for inorganic phosphate mobilizing activity.

Glucagon administration is known to increase urinary inorganic phosphate (Pi) excretion. We have now confirmed that this effect also occurs in mice. While, at lower glucagon doses, phosphaturia was accompanied by a decrease in plasma Pi, at the highest dose of glucagon plasma Pi was not altered in spite of a massive increase in urinary Pi.

Management of hypercalcemia in relation to pathophysiology.

Hypercalcemia results from an imbalance between the fluxes of calcium (Ca) entering and leaving the extracellular space. The two most important influxes are the net intestinal Ca absorption and the net skeletal Ca resorption, whereas the renal excretion represents the main route of elimination. When produced in excess, various factors, particularly calciotropic hormones and cytokines, can disturb the Ca fluxes at intestinal, skeletal and renal tubular sites.

Parathyroid hormone-like changes in renal calcium and phosphate reabsorption induced by Leydig cell tumor in thyroparathyroidectomized rats.

The Leydig cell tumor Rice H-500 is a model of humoral hypercalcemia of malignancy. Hypercalcemia is considered to result mainly from increased bone resorption. However, a change in renal tubular reabsorption of calcium (Ca) as a contributing factor to the hypercalcemia has not yet been recognized.

Normalization of hypercalcemia associated with a decrease in renal calcium reabsorption in Leydig cell tumor-bearing rats treated with WR-2721.

The Rice-500 Leydig cell tumor (LCT) in Fischer rats is a model of humoral hypercalcemia of malignancy (HHM). In this model, the elevation of plasma calcium (Ca) does not result merely from an increased bone resorption, but also from an enhanced tubular Ca reabsorption (TRCa). We investigated the hypocalcemic response to WR-2721 [S-2,2-(3-aminopropylamino)-, ethylphosphorothioic acid] in LCT-bearing Fischer rats.

Compensatory renal growth: modulation by calcium PTH and 1,25-(OH)2D3.

To further elucidate the mechanisms by which compensatory renal growth (CRG) can be influenced by calcium and calcium regulating hormones, the influence of dietary calcium and phosphorus, parathyroid hormone (PTH) or 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) was evaluated in unilaterally nephrectomized (UNI-NX) rats. These animals were sacrificed three days after UNI-NX and CRG of the remaining kidney was assessed by kidney wt, RNA and DNA gains, and by 3H-thymidine incorporation. The degree of CRG was enhanced in animals given a low dietary calcium and, conversely, was decreased in those receiving a phosphorus-poor diet.

Effect of 1 alpha, 24(R)-dihydroxyvitamin D3 on calcium metabolism in the rat.

It has been suggested that 1 alpha, 24(R)-dihydroxyvitamin D3 (1,24(OH)2D3), a chemically synthesized vitamin D analogue, may have the property to enhance whole-body Ca retention and may thus be of use in osteoporosis. In order to test this hypothesis the main fluxes of Ca metabolism were measured in vitamin D-replete rats injected ip with 1.24(OH)2D3 at daily doses of 25, 50 and 100 pmol for 10 days.

Sodium-dependent phosphate transport inhibited by parathyroid hormone and cyclic AMP stimulation in an opossum kidney cell line.

In the present study we investigated the characteristics of the transport of inorganic phosphate (Pi) in an opossum kidney cell line endowed with parathyroid hormone (PTH) receptors. In confluent epithelial cell culture, a Na-dependent Pi transport (NaPiT) was identified. Preincubation for 1 h with bovine (b)PTH(1-34) at 10(-7) M inhibited the NaPiT from 2.